Adaptation to low oxygen conditions is essential for maintaining homeostasis and viability in oxygen-consuming multi-cellular tissues, including solid tumors. Central in these processes are the hypoxia-inducible transcription factors, HIF-1 and HIF-2, controlling genes involved in e.g. glucose metabolism and neovascularization. Tumor hypoxia and HIF expression have also been associated with a dedifferentiated phenotype and increased aggressiveness. In this report we show that the MAX interactor-1 (MXI1) gene is directly regulated by HIF proteins in neuroblastoma and *** cancer cells. HIF binding and transactivation was detected within MXI1 gene regulatory sequences in the vicinity of the MXI1-0 promoter, leading to rapid induction of the alternate MXI1-0 isoform followed by a long-term induction of both the MXI1-0 and MXI1 isoforms. Importantly, knock-down of MXI1 had limited effect on MYC/MYCN activity under hypoxia, an observation that might be related to the different functional attributes of the two MXI1 isoforms.